Tuberculosis is the leading cause of death due to an infectious disease in the world. As a pulmonary pathogen, the initial interaction between the causative bacterium Mycobacterium tuberculosis (M.tb) and the human host is in the lung where surfactant, epithelial cells, and alveolar macrophages are located. This initial interaction between these components of the alveolus and M.tb dictate the outcome of infection. The understanding of this process is limited, but critical in this disease. This five year award will provide insight into the pathogenesis of tuberculosis, specifically in the role that surfactant components play in the early host response to this host-adapted microorganism. The specific aims are to: characterize the binding of surfactant protein D (SP-D) to virulent and attenuated M.tb strains, and their major surface components, and to determine the impact of this binding on bacterial agglutination; determine if SP-D alone or in conjunction with surfactant protein A (SP-A), and the major surfactant phospholipid, dipalmitoyl phosphatidylcholine (DPPC), influences the phagocytosis of M.tb by macrophages; determine if SP-D, SP-A, and DPPC influence the intracellular survival of M.tb in the macrophage, and to examine whether this is the result of altered cellular responses such as phagosome-lysosome fusion or the oxidative burst; and, determine if SP-D, SP-A, and DPPC influence the M.tb-pulmonary epithelial cell interaction. These specific aims will be accomplished using in vitro techniques available at the primary laboratory and through collaborative efforts. The candidate is a fellow in the Division of Pulmonary, Critical Care, and Occupational Medicine. Through an intense course of didactic and laboratory study, he will define the essential role that surfactant components play in the host defense response to M.tb using methods of microbiology, immunology, biochemistry, molecular biology, and cell physiology. He will determine the role that SP-A, SP-D, and DPPC, have in regulating the immune response of macrophages and epithelial cells to this intracellular pathogen. The proposed work will be performed at the University of Iowa, a well-known leader in biomedical research. The work to be performed encompasses the Division of Infectious Diseases and the Division of Pulmonary, Critical Care, and Occupational Medicine, as well as various departments from the College of Medicine. Laboratory facilities are at the Iowa City Veterans Administration Center, and the University of Iowa. The candidate, mentors, advisory committee, and collaborators will work closely to achieve the goals of this proposed award: to define critical interactions between the human pathogen M.tb and the host, and for the principal investigator to become an accomplished independent biomedical investigator.